Extracellular microRNAs (miRNA) are transported between organs in plasma by protective carriers, including high-density-lipoproteins (HDL). Cardiovascular disease (CVD) represents a significant health and financial burden to our society; however, miRNAs are a new class of drug targets that may be used to treat atherosclerosis. Our published reports and preliminary data suggest that HDL-miRNAs likely serve as biological hormones that regulate systemic homeostasis and have potential to be controlled to treat or prevent CVD. Atherosclerosis is a complex pathophysiology mediated by extensive cell-to-cell communication and gene regulation. The main objectives of this study are to define novel HDL-miRNA intercellular communication mechanisms and the physiological impact of HDL-miRNA communication in CVD. To complete these goals we will, i.) Map the distribution of HDL-miRNA communication and gene regulation, ii.) Identify novel HDL-miRNA target genes associated with inflammation and metabolism, iii.) Determine the role HDL-miR-223 plays in atherosclerosis, and iv.) Control HDL-miRNA communication to treat metabolic dysregulation and atherosclerosis. Collectively, this study will provide remarkable and fundamental insight into HDL biology, and defines the functional relevance and consequences of HDL-miRNA communication in health and disease in animals and humans. As constructed, these studies will take advantage of current concepts in lipoprotein biology and use state-of-the art methods and equipment, including extensive use of high-throughput sequencing.